The synthesis and screening of small molecule combinatorial libraries has become an important new technology for drug discovery. (For reviews see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385. (c) Moos, W. H.; Green, G. D.; Pavia, M. R. Recent Advances in Generation of Molecular Diversity. in Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press, Inc.; San Diego, Calif., 1993; Vol. 28, pp. 315-324. (d) Ecker, D. J.; Crooke, S. T. Biotechnology 1995, 13, 351. (e) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele J. Tetrahedron 1995, 51, 8135. (f) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (g) Herkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron, 1996, 52, 4527. (h) Fruchtel, J. S.; Jung, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 17.) A convenient format for the generation of these libraries is synthesis of organic compounds on a solid phase. Solid phase synthesis is especially useful for reactions where excess reagents can be used to drive the reactions to completion. The excess reagents and soluble byproducts can be easily removed. (See, for example: (a) Kurth, M. J.; Randall, L. A. A.; Chen, C.; Melander, C.; Miller, R. B. J. Org. Chem. 1994, 59, 5862. (b) Hiroshige, M.; Hauske, J. R.; Zhou, P. J. Am. Chem. Soc. 1995, 117, 11590. (c) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819. (d) Goff, D. A.; Zuckermann, R. N. J. Org. Chem. 1995, 60, 5744. (e) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60, 6006. (f) Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427. (g) Forman, F. W.; Sucholeiki, I. J. Org. Chem. 1995, 60, 523. a) Holmes, C. P.; Jones, D. G. J. Org. Chem. 1995, 60, 2318. (i) Holmes, C. P.; Chinn, J. P.; Look, G. C.; Gordon, E. M.; Gallop, M. A. J. Org. Chem. 1995, 60, 7328.) Another important feature of solid phase synthesis is allowing "split and combine" methodology to be employed for library construction. Thus, generating diverse combinatorial libraries requires the development of solid phase syntheses of biologically active molecules on solid support, and the exploration of such synthetic methodologies for preparation of libraries.
Often compounds isolated from natural products have biological activity. For example, derivatives prepared from natural products, nucleic acids, peptides, proteins, and mimics thereof have remarkable biological activities. (See: Boyd, G. V. In Comprehensive Heterocyclic Chemistry, Vol. 6; Part 4B, Katritzky, A. R.; Rees, C. W., Eds.; Pergammon: Oxford, 1984; p178.)
Preparation of high molecular weight organic compounds, such as, for example, oligonucleotides, can be synthetically challenging. Often multiple synthetic steps are required to prepare the desired compounds. As a consequence of multistep syntheses, reaction conditions utilized to form oligonucleotides can facilitate degradation of the remaining molecular functionality. Additionally, synthetic manipulation of an oligonucleotide can cause the oligonucleotide to fragment into shorter lower molecular weight portions, thereby reducing the yield of the desired compound.